The vascular endothelium participates in the regulation of regional blood flow by modulating the release of endothelium-dependent relaxing factor, of which nitric oxide (NO) is a major component. Plasma levels of nitrate, the stable end-product of NO, are significantly increased in patients with chronic heart failure; however, the site of NO production is not completely understood.
Immunohistochemical studies have revealed that inducible NO synthase (iNOS) expression is significantly increased in ventricular myocytes isolated from severely failing hearts, suggesting that the cardiac release of NO is increased in patients with chronic heart failure. The coronary artery and atrial and ventricular myocytes of failing hearts have been suggested as sources of NO. INOS-derived NO blunts the responsiveness to (5-adrenergic stimulation, induces apoptosis, and has cytotoxic effects, all of which may impair cardiac function.
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Because NO reduces myocardial contractility and regulates systemic vascular resistance in chronic heart failure, it is important to estimate its release from the failing heart. Node et al measured NO levels in simultaneous blood samples from the great cardiac vein and aortic artery in patients with mild-to-severe heart failure, and found an increase that correlated with the severity of both heart failure and cardiac dysfunction.
(Figures 1 and 2). Cardiac NO levels were also more sensitive to heart failure severity than peripheral venous NO, especially in mild heart failure.
Catecholamines, renin-angiotensin, and cytokines are all involved in the pathophysiology of heart failure, but the cytokine system, and specifically tumor necrosis fac-tor-a (TNF-a), has a particular role in iNOS expression. Evaluating the association between monocytic iNOS synthase expression, TNF-a activation, neurohormones, and other clinical parameters in heart failure, Comini et al observed: (i) an increase, related to clinical severity, in antigenic TNF-a and its soluble receptors; (ii) expression of monocytic iNOS in heart failure patients, but not in healthy controls; and (iii) a close association between iNOS expression, New York Heart Association class, TNF-a, and its soluble receptors.
Cytokine-mediated transcriptional activation may subsequently increase plasma NO levels. Moreover, because the cardiac release of norepinephrine is increased in chronic heart failure and because aj-adrenoceptor activity regulates the release of NO, neurohormones may also modify NO release in failing hearts.
In conclusion, iNOS appears to be expressed in the circulating monocytes of patients with severe congestive heart failure due to TNF-a system activation. The cardiac levels of iNOS-derived NO may increase with the severity of both heart failure and cardiac dysfunction.
Hyperbilirubinemia in heart failure: what should be done?
Hyperbilirubinemia is due to abnormal formation, transport, metabolism, and/or excretion of bilirubin. See Table for the main causes.
Differential diagnosis is mandatory before attributing hyperbilirubinemia to a cardiac cause in a heart failure patient.
Chronic hepatic dysfunction in heart failure.
Hepatic dysfunction is likely when right atrial pressure exceeds 10 mm Hg and the cardiac index declines below 1.5 L/min/m2. Often associated with congestive hepatomegaly and cardiac cirrhosis, it is characterized by abnormal enzyme levels (eg, aspartate aminotransferase [AST], alanine aminotransferase, and lactic dehy-